The objective of this K23 proposal is to enable an early-career investigator to establish an independent research program in translational neuroscience of HIV infection and alcohol use disorders. The K23 studies focus on three high-priority areas within NIAAA's strategic plan: 1) HIV-alcohol interactions; 2) the gut-brain axis; and 3) immune effects of alcohol.8-10 A major contributor to chronic systemic inflammation in HIV is microbial translocation (MT), the abnormal movement of gut products into circulation.11, 12 Heavy alcohol use also is known to cause MT and inflammation.13-15 In HIV, MT and immune activation biomarkers independently predict cognitive impairment, suggesting these processes contribute to neurodegeneration.16-18 Indeed, degeneration of the brain's white matter is a hallmark injury of both HIV infection and heavy alcohol use, independently and in co-occurrence.19-23 White matter degeneration poses a serious health risk for people living with HIV, particularly those who engage in hazardous drinking. Study 1 will investigate whether heavy drinking compounds MT and immune activation in HIV infection and whether these processes predict white matter degeneration over time. Study 1 combines new immune biomarker assays with secondary analysis of neuroimaging and substance use data from a longitudinal study by Brown's Alcohol Research Center on HIV (ARCH; 2P01AA019072). In 180 participants stratified on HIV and heavy drinking status (42 control; 68 HIV only; 34 ETOH only; 36 HIV+ETOH), plasma samples and alcohol use data were collected at baseline, 3, 6, and 12 months. Brain white matter was assessed using diffusion tensor imaging at baseline and 12 months. Using reposited plasma samples, the K23 project will test the hypothesis that specific markers of MT and immune response will predict WM degeneration in heavy drinking, HIV, and their comorbidity. Results will contribute to 1) development of peripheral biomarkers of HIV- and alcohol-related brain damage; 2) guidelines for safer alcohol use specifically in people living with HIV. Study 2 will address critical knowledge gaps on alcohol's acute immune effects by investigating two key contextual factors: 1) alcohol dose and 2) habitual heavy drinking, linked by previous research to intestinal hyperpermeability.13, 24, 25 Study 2 uses a 2 x 3 design with drinking status (light, heavy) as between-subjects factor and beverage condition (placebo, 0.35 g/kg, 0.60 g/kg) as within-subjects factor. Thirty participants (15 light, 15 heavy drinkers) will receive all conditions in randomized, counterbalanced fashion. Change in biomarkers of MT and immune response will be measured. Study 2 with HIV-negative individuals will provide normative data on alcohol-induced immune perturbations to inform planned future studies with HIV-positive individuals. The candidate has assembled a superbly qualified mentor team with expertise in neuroscientific, behavioral, and immunological research on HIV and alcohol use. The K23 training plan will enable the applicant to establish an independent career in translational neuroscience research on HIV-alcohol interactions through mentored training in 1) HIV-specific clinical research; 2) immune processes in HIV and alcohol use; 3) HIV neurobiology of HIV; 4) mechanistic, lab-based alcohol research.